Study Design: This is a single arm trial of ibrutinib in previously treated, relapsed, or refractory CLL patients with del(17p13.1). The primary endpoint is IWCLL 2008 overall response (partial + complete) response, and secondary endpoints are safety, progression-free survival (PFS), and overall survival.

Rationale: The gene locus of the master tumor suppressor, p53, is chromosome 17p13.1, and patients with a CLL clone deficient in p53 because of deletion (del) involving that locus have a particularly poor prognosis. Although patients with del(17p13.1) often respond to cytotoxic chemotherapy in combination with rituxan, responses are usually not durable, and, typically, response duration becomes progressively shorter with successive treatments. B-cell receptor (BCR) signaling has been shown to be an important driver of proliferation in high-risk CLL. The Bruton agammaglobulinemia tyrosine kinase (BTK) is an essential component of BCR signaling, and ibrutinib, an irreversible inhibitor of BTK, has demonstrated significant activity in relapsed CLL, including patients with del(17p13.1). The current trial builds upon those observations by exclusively targeting treatment of patients with CLL or SLL with del(17p13.1) with the aim of identifying effective therapy for this poor prognosis group.

Comment: As hematologists, we have been mesmerized by the transformative power of imatinib in the treatment of CML. That CLL is not analogous to CML, in that there is no single, common genetic aberration equivalent to BCR-ABL that drives the disease, made the prospect of identifying a targeted drug for CLL equivalent in efficacy to imatinib unlikely. However, recognition of the importance of BCR signaling in the pathobiology of CLL and subsequent development of BCR signaling pathway inhibitors, such as ibrutinib, has created a sense of optimism in the field that effective targeted therapy is not only feasible but imminent. Large, completed phase I/II studies with ibrutinib in relapsed CLL have shown responses in approximately 71 percent of patients with another 18 percent benefiting from disease control but with persistent lymphocytosis.

The toxicity of ibrutinib appears modest with the major adverse effects being low-grade diarrhea, dyspepsia, infection, and rash. Notably, patients have been dosed beyond two years without observed late cumulative events. While many therapies do not work well in relapsed del(17p13.1) CLL, response to ibrutinib is similar (68%) to that observed in non-del(17p13.1) CLL, and remissions are durable with an estimated PFS at 26 months of 55 percent. Although comparative, randomized data are not yet available, this response rate and PFS duration are better than any other single-agent therapy previously tested in relapsed del(17p13.1) CLL. Physicians caring for patients with relapsed del(17p13.1) CLL should encourage patients to enroll in this study. Given that effective treatment of relapsed del(17p13.1) CLL represents an unmet medical need, the hope is that this trial will rapidly accrue patients and meet its designated endpoints, and by doing so, gain accelerated approval by the FDA for marketing of ibrutinib for this indication.